Dendritic cells (DCs) initiate primary and memory immune responses as well as activate innate immunity and therefore, play a pivotal role in immunotherapy [1]. Accounting for only 0.02-0.2% of the total white blood cells, the number of DCs that can be isolated from peripheral blood is limited [2]. When cultured with supplement of GM-CSF and IL-4, PBMCs or CD14-selected monocytes generate DCs at about 50% of the starting cell number. Furthermore, patients with cancer or chronic infections often suffer from a compromised immune system with increased myeloid suppressor cells and dysfunctional DCs [3-9].
The developmental origin and tissue distribution of various lineages of human versus mouse DCs are still not well defined [10-15]. Transgenic mouse studies have reported several transcription factors implicated in regulating DC differentiation, which include zinc finger protein Ikaros, PU.1, relB, the helix-loop-helix (HLH) transcription factor inhibitor of DNA binding or differentiation 2 (Id2), interferon regulatory factor (IRF) 4 and 8, the Ets-domain transcription factor Spi-B, and the Notch family of proteins [14, 16]. In addition, growth factors such as Flt3L, KL, TPO, TNFα, GM-CSF, IL-3, IL-4, and IL-6 have been shown to promote development and maturation of DCs [17-20].
Growth factors such as KL and Flt3L appear to be strictly required for the generation of DC progenitors from HPCs in culture [21]. In the laboratory, GM-CSF and IL-4 are routinely used to generate DCs from adherent PBMCs, and GM-CSF and TNF-α can induce differentiation of HPCs into interstitial DCs and Langerhan's cells in 12-14 days [22]. GM-CSF and IL-15, on the other hand, drive DC differentiation from monocytes and bone marrow (BM) but the role of IL-15 in myeloid lineage development remains poorly understood [23, 24]. IL-15 is a member of the γC receptor family of cytokines which is expressed by a variety of cell types important to the survival of fibroblasts, T cells and natural killer cells. IL-15 has been shown to promote the survival of mature DCs through an autocrine antiapoptotic mechanism [25, 26], and IL-15-derived DCs are reported to display Langerhans cell-like features with strong T cell activation potential [23, 24, 27, 28].